Senescence of skeletal stem cells and their contribution to age-related bone loss.

Human aging is linked to bone loss, resulting in bone fragility and an increased risk of fractures. This is primarily due to an age-related decline in the function of bone-forming osteoblastic cells and accelerated cellular senescence within the bone microenvironment. Here, we provide a detailed discussion of the hypothesis that age-related defective bone formation is caused by senescence of skeletal stem cells, as they are the main source of bone forming osteoblastic cells and influence the composition of bone microenvironment. Furthermore, this review discusses potential strategies to target cellular senescence as an emerging approach to treat age-related bone loss.

Wölfel EM ，Fernandez-Guerra P ，Nørgård MØ ，Jeromdesella S ，Kjær PK ，Elkjær AS ，Kassem M ，Figeac F ... -  《-》

Aging of marrow stromal (skeletal) stem cells and their contribution to age-related bone loss.

Bellantuono I ，Aldahmash A ，Kassem M 《-》

Hypoxia-inducible factor-2α mediates senescence-associated intrinsic mechanisms of age-related bone loss.

Lee SY ，Park KH ，Lee G ，Kim SJ ，Song WH ，Kwon SH ，Koh JT ，Huh YH ，Ryu JH ... -  《-》

Inhibiting Cellular Senescence: A New Therapeutic Paradigm for Age-Related Osteoporosis.

Khosla S ，Farr JN ，Kirkland JL 《-》

DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age.

Age-related bone loss in mice results from a decrease in bone formation and an increase in cortical bone resorption. The former is accounted by a decrease in the number of postmitotic osteoblasts which synthesize the bone matrix and is thought to be the consequence of age-dependent changes in mesenchymal osteoblast progenitors. However, there are no specific markers for these progenitors, and conclusions rely on results from in vitro cultures of mixed cell populations. Moreover, the culprits of such changes remain unknown. Here, we have used Osx1-Cre;TdRFP mice in which osteoprogenitors express the TdRFP fluorescent protein. We report that the number of TdRFP-Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP-Osx1 cells from old mice exhibited markers of DNA damage and senescence, such as γH2AX foci, G1 cell cycle arrest, phosphorylation of p53, increased p21CIP1 levels, as well as increased levels of GATA4 and activation of NF-κB - two major stimulators of the senescence-associated secretory phenotype (SASP). Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro-osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.

Kim HN ，Chang J ，Shao L ，Han L ，Iyer S ，Manolagas SC ，O'Brien CA ，Jilka RL ，Zhou D ，Almeida M ... -  《-》